Aim\nMethods\nResults\nDiscussion\nSystematic Review Registration\nTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment.... Show moreAim\nMethods\nResults\nDiscussion\nSystematic Review Registration\nTraditionally, early phase clinical trials in oncology have been performed in patients based on safety risk-benefit assessment. Therapeutic transition to immuno-oncology may open new opportunities for studies in healthy volunteers, which are conducted faster and are less susceptible to confounders. Aim of this study was to investigate to what extent this approach is utilized and whether pharmacodynamic endpoints are evaluated in these early phase trials. We conducted a comprehensive review of clinical trials with healthy volunteers using immunotherapies potentially relevant for oncology.\nLiterature searches according to PRISMA guidelines and after registration in PROSPERO were conducted in PubMed, Embase, Web of Science and Cochrane databases with the cut-off date 20 October 2020, using search terms of relevant targets in immuno-oncology. Articles describing clinical trials with immunotherapeutics in healthy volunteers with a mechanism relevant for oncology were included. "Immunotherapeutic" was defined as compounds exhibiting effects through immunological targets. Data including study design and endpoints were extracted, with specific attention to pharmacodynamic endpoints and safety.\nIn total, we found 38 relevant immunotherapeutic compounds tested in HVs, with 86% of studies investigating safety, 82% investigating the pharmacokinetics (PK) and 57% including at least one pharmacodynamic (PD) endpoint. Most of the observed adverse events (AEs) were Grade 1 and 2, consisting mostly of gastrointestinal, cutaneous and flu-like symptoms. Severe AEs were leukopenia, asthenia, syncope, headache, flu-like reaction and liver enzymes increase. PD endpoints investigated comprised of cytokines, immune and inflammatory biomarkers, cell counts, phenotyping circulating immune cells and ex vivo challenge assays.\nHealthy volunteer studies with immuno-oncology compounds have been performed, although not to a large extent. The integration of healthy volunteers in well-designed proof-of-mechanism oriented drug development programs has advantages and could be pursued more in the future, since integrative clinical trial protocols may facilitate early dose selection and prevent cancer patients to be exposed to non-therapeutic dosing regimens.\nhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=210861, identifier CRD42020210861. Show less
Jones, C.; Smith-MacDonald, L.; Veelen, N. van; VanderLaan, A.; Kaneva, Z.; Dunleavy, R.S.; ... ; Bremault-Phillips, S. 2022
Background As provisions of mental healthcare services to military and veteran populations increases the risk to service providers developing secondary traumatic stress (STS), efforts are needed to... Show moreBackground As provisions of mental healthcare services to military and veteran populations increases the risk to service providers developing secondary traumatic stress (STS), efforts are needed to examine the impact of delivering novel interventions which may include 3MDR. As a virtual-reality supported intervention, 3MDR exposes the patient, therapist and operator to graphic and sensory stimuli (i.e. narratives, imagery, smells, and music) in the course of the intervention. 3MDR is actively being researched at multiple sites internationally within military and veteran populations. It is, therefore, crucial to ensure the safety and wellbeing of 3MDR therapists and operators who are exposed to potentially distressing sensory stimuli. Objective The purpose of this study is to qualitatively examine the impact and experiences of STS amongst therapists and operators in delivering 3MDR. For this study, impact will be defined as therapists or operators experiencing perceived STS as a result of delivering 3MDR. Methods This exploratory qualitative study recruited 3MDR therapists and operators (N = 18) from Canada, the Netherlands, the United Kingdom, and the United States who had previously delivered 3MDR therapy. Telephone or video-conferencing interviews were used to gather data that was subsequently transcribed and thematically analyzed. Results Four themes emerged among the therapists (n = 13) and operators (n = 5): (1) personal cost and benefits of 3MDR, (2) professional paradox of a 3MDR therapist, (3) perceived effect of 3MDR on patients, and (4) recommendations for future 3MDR use. Conclusions STS was not noted to be a significant challenge for 3MDR therapists and operators. Future research may investigate optimal means of providing training and ongoing support for 3MDR therapists and operators. Show less
Abstract The Egyptian-Greek contact situation has lasted almost a thousand years and many documents have been preserved to us from this period. In this paper, we apply a new quantitative approach... Show moreAbstract The Egyptian-Greek contact situation has lasted almost a thousand years and many documents have been preserved to us from this period. In this paper, we apply a new quantitative approach to this rich corpus of documentary papyri to map the relationships between the linguistic variables (the variant spellings) and several non-linguistic variables. A multidimensional scaling of the co-occurrences of the linguistic variables shows that there is a strong association between most of the Greek variant spellings that can be explained by Egyptian phonological transfer, while others do not typically co-occur with them. Several new linguistic variables not yet connected to Egyptian phonological transfer also show a strong relation with the first group of features, some of them representing the same phonological transfer processes. A comparison of the contexts in which these variables are used allows us to further substantiate this observation: several of the previously and newly Egyptian-associated variables turn out to have a strong correlation with bilingual Egyptian-Greek documents or occur in Egyptian dominated environments. The spelling variants are chronologically dependent and different features are typically associated with different historical periods illustrating changes taking place in the Egyptian Greek contact variety over time. A multiple correspondence analysis shows that the variables strongly interact, illustrating the importance of a multifactorial approach combining various linguistic and non-linguistic factors. Show less
When Lucretius invokes Calliope as his dux at the end of the proem to Book VI (92-95), the echo of I 1 in VI 94 reinforces a more general correspondence between Calliope and Venus, whom Lucretius... Show moreWhen Lucretius invokes Calliope as his dux at the end of the proem to Book VI (92-95), the echo of I 1 in VI 94 reinforces a more general correspondence between Calliope and Venus, whom Lucretius had invoked as his socia in the proem to Book I (24). This paper argues that the two goddesses share the same double identity, as they both represent a twofold aspect of the poem, namely the profound interdependence of form and content. This twofold aspect is cunningly embodied in an interlingual pun on Epicurus’ name, which makes him an ἐπίκουρος to his own philosophy. Show less
Experiments with indigenous languages as medium of instruction have been ongoing in francophone Africa. These experiments have not been generalized to all schools by educational authorities and... Show moreExperiments with indigenous languages as medium of instruction have been ongoing in francophone Africa. These experiments have not been generalized to all schools by educational authorities and have been limited to the first few years of primary education. A more generalized approach to using indigenous languages as medium of instruction can contribute to improve the outcomes of education. However, when is such a development likely to occur and which languages should be chosen? This article explores these questions using the case of Burkina Faso as an example. We show that it will be practically possible to use a limited number of indigenous languages as medium of instruction, rather than all languages spoken in the country. In order to do so, we introduce an approximate assessment of which languages are easy to learn and to teach, for speakers of which other languages. We demonstrate that a gradual transition towards indigenous languages will become a necessity if the present trend of increased participation in education continues into the future. In order for this to happen, careful planning and preparation will be essential; we conclude with a brief examination of what such planning and preparation might consist of. Show less
Background Cervical screening could be an appropriate routine moment to provide female smokers with tailored stop smoking advice. In Dutch general practice, cervical smears are performed by... Show moreBackground Cervical screening could be an appropriate routine moment to provide female smokers with tailored stop smoking advice. In Dutch general practice, cervical smears are performed by practice assistants. Objectives This study was performed in preparation for a randomised trial to identify potential barriers and enablers for a brief stop smoking strategy performed by trained practice assistants after routine cervical screening. Methods Between December 2016 and March 2017 three focus group meetings were held with ten practice assistants, three nurses, and six general practitioners to explore their views and expectations towards the proposed approach. We analysed data using thematic analysis. Identified factors are presented within the framework of the Social-Ecological Model. Results Potential barriers and enablers were identified at individual, interpersonal, and workplace levels. Practice assistants, nurses and GPs did not consider assistants to have a role in stop smoking care. They believed it is feasible to register smoking status but had reservations towards providing advice by assistants, for which knowledge and skills are needed. Practice assistants' own beliefs about smokers and smokers' response to stop smoking advice might influence how assistants and smokers interact. An explanation of why advice is given could help, provided assistants have enough time and experience with the smear. The nurses' availability and general practitioners' view on prevention might affect the delivery of the strategy by the assistant. Conclusion At individual, interpersonal, and workplace levels, several factors could influence the provision of a stop smoking strategy by a practice assistant. Show less
Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients... Show moreChimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients do not respond or relapse eventually. As an alternative to CAR T cells, T cells can be engineered to express a tumor-targeting T cell receptor (TCR). Due to HLA restriction of TCRs, CARs have emerged as a preferred treatment moiety when targeting surface antigens, despite the fact that functional differences between engineered TCR (eTCR) T and CAR T cells remain ill-defined. Here, we compared the activity of CAR T cells versus engineered TCR T cells in targeting the B cell malignancy-associated antigen CD20 as a function of antigen exposure. We found CAR T cells to be more potent effector cells, producing higher levels of cytokines and killing more efficiently than eTCR T cells in a short time frame. However, we revealed that the increase of antigen exposure significantly impaired CAR T cell expansion, a phenotype defined by high expression of coinhibitory molecules and effector differentiation. In contrast, eTCR T cells expanded better than CAR T cells under high antigenic pressure, with lower expression of coinhibitory molecules and maintenance of an early differentiation phenotype, and comparable clearance of tumor cells. Show less
Duijvenvoorde, A.C.K. van; Hoorn, J. van; Blankenstein, N.E. 2022
Adolescent decision-making has been characterized as risky, and a heightened reward sensitivity may be one of the aspects contributing to riskier choice-behavior. Previous studies have targeted... Show moreAdolescent decision-making has been characterized as risky, and a heightened reward sensitivity may be one of the aspects contributing to riskier choice-behavior. Previous studies have targeted reward-sensitivity in adolescence and the neurobiological mechanisms of reward processing in the adolescent brain. In recent examples, researchers aim to disentangle the contributions of risk- and reward-sensitivity to adolescent risk-taking. Here, we discuss recent findings of adolescent's risk preferences and the associated neural mechanisms. We highlight potential frameworks that target individual differences in risk preferences in an effort to understand adolescent risk-taking, and with an ultimate goal of leveraging undesirable levels of risk taking. Show less
The Programme on Ecosystem Change and Society (PECS) was established in 2011, and is now one of the major international social-ecological systems (SES) research networks. During this time, SES... Show moreThe Programme on Ecosystem Change and Society (PECS) was established in 2011, and is now one of the major international social-ecological systems (SES) research networks. During this time, SES research has undergone a phase of rapid growth and has grown into an influential branch of sustainability science. In this Perspective, we argue that SES research has also deepened over the past decade, and helped to shed light on key dimensions of SES dynamics (e.g. system feedbacks, aspects of system design, goals and paradigms) that can lead to tangible action for solving the major sustainability challenges of our time. We suggest four ways in which the growth of place-based SES research, fostered by networks such as PECS, has contributed to these developments, namely by: 1) shedding light on transformational change, 2) revealing the social dynamics shaping SES, 3) bringing together diverse types of knowledge, and 4) encouraging reflexive researchers. Show less
INTRODUCTION\nMETHODS\nRESULTS\nDISCUSSION\nSaudi Arabia experiences elevated levels of body-shape dissatisfaction which might be related to the increased thin ideal. Studies on body-shape... Show moreINTRODUCTION\nMETHODS\nRESULTS\nDISCUSSION\nSaudi Arabia experiences elevated levels of body-shape dissatisfaction which might be related to the increased thin ideal. Studies on body-shape dissatisfaction are scarce, mainly because adapted assessment tools are unavailable. This study describes the Saudi-Arabic adaptation of the Body Shape Questionnaire (BSQ34), preliminary examines the psychometric properties and provides normative data.\nThe BSQ34 was administered in a convenience community sample (N = 867) between April 2017 and May 2018. Receiver-operating-characteristic curve analysis was used to establish discriminant validity, in a subsample (N = 602) in which the Eating Disorder Examination-Shape concern, was administered, the factor structure investigated with confirmatory-factor analyses and T-scores and percentile scores were determined.\nThe BSQ34 discriminated well between low and high levels of body-shape dissatisfaction (area-under-the-curve value = 0.93), had high internal consistency and a unidimensional factor structure, and 23.9% appeared at risk for body-shape dissatisfaction. Analyses were repeated for the shortened BSQ8C, which yielded similar results.\nThe results indicated that the BSQ34 and BSQ8C appeared suitable measurement tools to screen for body-shape dissatisfaction in a Saudi convenience community sample, mainly comprised young, unmarried, and highly educated women. The BSQ34 supplies more information on the type of concerns respondents have, which is worthwhile when the measure is used in a clinical setting; the BSQ8C is recommended as a short screener. As body-shape dissatisfaction is viewed as a risk factor for the development of eating disorder symptoms, screening for body-shape dissatisfaction with reliable tools is important to detect individuals at risk for eating disorder symptoms and may suggest subsequent preventive steps. Show less
INTRODUCTION\nMETHODS\nRESULTS\nCONCLUSIONS\nThe outcomes anxiety and depression are measured frequently by healthcare providers to assess the impact of a disease, but with numerous instruments.... Show moreINTRODUCTION\nMETHODS\nRESULTS\nCONCLUSIONS\nThe outcomes anxiety and depression are measured frequently by healthcare providers to assess the impact of a disease, but with numerous instruments. PROMIS item banks provide an opportunity for standardized measurement. Cross-cultural validity of measures and the availability of reference values are prerequisites for standardized measurement.\nPROMIS Anxiety and Depression item banks were completed by 1002 representative Dutch persons. To evaluate cross-cultural validity, data from US participants in PROMIS wave 1 were used and differential item functioning (DIF) was investigated, using an iterative hybrid of logistic regression and item response theory. McFadden's pseudo R2-change of 2% was the critical threshold. The impact of any DIF on full item banks and short forms was investigated. To obtain Dutch reference values, T-scores for anxiety and depression were calculated for the complete Dutch sample, and age-group and gender subpopulations. Thresholds corresponding to normal limits, mild, moderate and severe symptoms were computed.\nIn both item banks, two items had DIF but with minimal impact on population level T-scores for full item banks and short forms. The Dutch general population had a T-score of 49.9 for anxiety and 49.6 for depression, similar to the T-scores of 50.0 of the US general population. T-scores for age-group and gender subpopulations were also similar to T-scores of the US general population. Thresholds for mild, moderate and severe anxiety and depression were set to 55, 60 and 70, identical to US thresholds.\nThe limited number of items with DIF and its minimal impact, enables the use of standard (US) item parameters and comparisons of scores between Dutch and US populations. The Dutch reference values provide an important tool for healthcare professionals and researchers to evaluate and interpret symptoms of anxiety and depression, stimulating the uptake of PROMIS measures, and contributing to standardized outcome measurement. Show less
We aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the... Show moreWe aimed at investigating host-virus co-metabolism during SARS-CoV-2 infection. Therefore, we extended comprehensive sex-specific, whole-body organ resolved models of human metabolism with the necessary reactions to replicate SARS-CoV-2 in the lung as well as selected peripheral organs. Using this comprehensive host-virus model, we obtained the following key results: 1. The predicted maximal possible virus shedding rate was limited by isoleucine availability. 2. The supported initial viral load depended on the increase in CD4+ T-cells, consistent with the literature. 3. During viral infection, the whole-body metabolism changed including the blood metabolome, which agreed well with metabolomic studies from COVID-19 patients and healthy controls. 4. The virus shedding rate could be reduced by either inhibition of the guanylate kinase 1 or availability of amino acids, e.g., in the diet. 5. The virus variants differed in their maximal possible virus shedding rates, which could be inversely linked to isoleucine occurrences in the sequences. Taken together, this study presents the metabolic crosstalk between host and virus and emphasises the role of amino acid metabolism during SARS-CoV-2 infection, in particular of isoleucine. As such, it provides an example of how computational modelling can complement more canonical approaches to gain insight into host-virus crosstalk and to identify potential therapeutic strategies. Show less
While facility births are increasing in many low-resource settings, quality of care often does not follow suit; maternal and perinatal mortality and morbidity remain unacceptably high. Therefore,... Show moreWhile facility births are increasing in many low-resource settings, quality of care often does not follow suit; maternal and perinatal mortality and morbidity remain unacceptably high. Therefore, realistic, context-tailored clinical support is crucially needed to assist birth attendants in resource-constrained realities to provide best possible evidence-based and respectful care. Our pilot study in Zanzibar suggested that co-created clinical practice guidelines (CPGs) and low-dose, high-frequency training (PartoMa intervention) were associated with improved childbirth care and survival. We now aim to modify, implement, and evaluate this multi-faceted intervention in five high-volume, urban maternity units in Dar es Salaam, Tanzania (approximately 60,000 births annually). This PartoMa Scale-up Study will include four main steps: I. Mixed-methods situational analysis exploring factors affecting care; II. Co-created contextual modifications to the pilot CPGs and training, based on step I; III. Implementation and evaluation of the modified intervention; IV. Development of a framework for co-creation of context-specific CPGs and training, of relevance in comparable fields. The implementation and evaluation design is a theory-based, stepped-wedged cluster-randomised trial with embedded qualitative and economic assessments. Women in active labour and their offspring will be followed until discharge to assess provided and experienced care, intra-hospital perinatal deaths, Apgar scores, and caesarean sections that could potentially be avoided. Birth attendants' perceptions, intervention use and possible associated learning will be analysed. Moreover, as further detailed in the accompanying article, a qualitative in-depth investigation will explore behavioural, biomedical, and structural elements that might interact with non-linear and multiplying effects to shape health providers' clinical practices. Finally, the incremental cost-effectiveness of co-creating and implementing the PartoMa intervention is calculated. Such real-world scale-up of context-tailored CPGs and training within an existing health system may enable a comprehensive understanding of how impact is achieved or not, and how it may be translated between contexts and sustained. Trial registration number: NCT04685668 Show less
